Design of Experiments-Guided Development of Gallic Acid-Loaded Transethosomal Chitosan Gels

Background/Objectives: Gallic acid (GA) is a natural phenolic acid with reported antioxidant, anti-inflammatory, and antibacterial properties, but its limited skin permeation restricts its topical application. Although previous studies have demonstrated the potential of transethosomal formulations to enhance dermal GA delivery, their liquid dispersion form hinders practical topical use. Methods: The aim of this study was to investigate the effects of chitosan molecular weight, chitosan concentration, and transethosome proportion on the GA release, pH, and spreadability of GA-loaded transethosomal chitosan gel using a Design of Experiments (DoE)-guided approach. First, transethosomes were synthesized using the cold method and assessed for physicochemical properties, in vitro permeability, and physical stability. Next, transethosomal gels were prepared based on a three-level full factorial DoE model. The results were analyzed using polynomial regression modeling and sweet spot analysis. The model-predicted exploratory sweet-spot region was experimentally verified, followed by additional assessments of drug content and content uniformity, rheological properties, and short-term physical stability. Results: GA-loaded transethosomes had a diameter of 167.3 ± 9.9 nm, an encapsulation efficiency of 71.6 ± 5.7%, and substantially higher in vitro permeability across Strat-M® synthetic membranes (2520.77 ± 66.93 µg/cm2 within 24 h) compared to aqueous GA solution. After incorporation into chitosan gel, GA release at 6 h ranged from 65.5% to 93.2%. Formulations showed pH values of 3.93–4.46 and spreadability of 12.6–122.7 cm2. Increased chitosan concentration reduced GA release and increased pH toward the target range, while higher chitosan concentration and molecular weight restricted spreading. Rheological characterization revealed shear-thinning behavior. Conclusions: The DoE-guided approach supported exploratory screening of GA-loaded transethosomal chitosan gels and provided insights into the relationships between formulation composition, GA release, pH, and spreadability.